Novel orphan receptors

ABSTRACT

The present invention provides for nucleic acid sequences that encode novel mammalian receptor polypeptides, designated OCR1. The invention also provides assay systems that may be used to detect and/or measure ligands that bind the MAMMALIAN OCR1 gene product. The present invention also provides for diagnostic and therapeutic methods based on the interaction between MAMMALIAN OCR1 and agents that initiate signal transduction through binding to MAMMALIAN OCR1. In a specific embodiment, the MAMMALIAN OCR1 may HUMAN OCR1 or MOUSE OCR1.

[0001] Throughout this application various publications are referenced.The disclosures of these publications in their entireties are herebyincorporated by reference into this application.

INTRODUCTION

[0002] The field of this invention is polypeptide molecules whichregulate cell function, nucleic acid sequences encoding thepolypeptides, and methods of using the nucleic acid sequences and thepolypeptides. The present invention provides for novel receptormolecules, their use and assay systems useful for identifying novelligands that interact with these receptors.

BACKGROUND OF THE INVENTION

[0003] The ability of ligands to bind cells and thereby elicit aphenotypic response such as development, differentiation, growth,proliferation, survival and regeneration in such cells is often mediatedthrough transmembrane receptors. The extracellular portion of eachreceptor is generally the most distinctive portion of the molecule, asit provides the protein with its ligand-recognizing characteristic. Inthe case of receptor tyrosine kinases (RTKs), binding of a ligand to theextracellular domain results in signal transduction via an intracellulartyrosine kinase catalytic domain which transmits a biological signal tointracellular target proteins. The particular array of sequence motifsof this intracellular tyrosine kinase catalytic domain determines itsaccess to potential kinase substrates (Mohammadi, et al., 1990, Mol.Cell. Biol. 11:5068-5078; Fantl, et al., 1992, Cell 69:413-413). Forinstance, growth hormone (GH) and prolactin (PRL) receptor signaltransduction is mediated by a signaling system that links activation ofthe GH or PRL receptor at the cell surface to changes in genetranscription in the nucleus. This pathway utilizes the Jak/Stat (Januskinase/signal transducer and activator of transcription) pathway used bymany growth factors and cytokines (See Watson, et al., 1996, Rev.Reprod. 1:1-5).

[0004] The tissue distribution of a particular receptor within higherorganisms provides relevant data as to the biological function of thereceptor. The RTKs for some growth and differentiation factors, such asfibroblast growth factor (FGF), are widely expressed and thereforeappear to play some general role in tissue growth and maintenance.Members of the Trk RTK family (Glass & Yancopoulos, 1993, Trends in CellBiol. 3:262-268) of receptors are more generally limited to cells of thenervous system, and the neurotrophins which bind these receptors promotethe differentiation of diverse groups of neurons in the brain andperiphery (Lindsay, R. M, 1993, in Neurotrophic Factors, S. E. Loughlin& J. H. Fallon, eds., pp. 257-284 (San Diego, Calif., Academic Press).Prolactin (PRL), an anterior pituitary hormone, is encoded by a memberof the growth hormone/prolactin/placental lactogen gene family. Inmammals, it is primarily responsible for the development of the mammarygland and lactation. In addition to its classical effects in the mammarygland, PRL has been shown to have a number of other actions, all ofwhich are initiated by an interaction with transmembrane receptorslocated on the cell surface and widely distributed in a number oftissues. Studies have shown that PRL receptor expression levels aredifferentially regulated in different tissues (Zhuang and Dufau, 1996,J. Biol. Chem. 271:10242-10246; Moldrup, et al., 1996, Mol. Endocrinol.10:661-671; Borg, et al., 1996, Eur J. Endocrinol. 134:751-757). Forexample, in rat liver, a tissue with a relatively high level of PRLbinding, receptor levels vary during the different phases of the estrouscycle, increase during pregnancy, and are markedly stimulated byestrogens. Furthermore, PRL plays a major role in the regulation ofexpression of the PRL receptor, inducing both up- and down-regulationdepending on PRL concentration and duration of exposure (See, forexample, Di Carlo, et al., 1995, Endocrinology 136:4713-4716; Matsudaand Mori, 1996, Zoolog. Sci. 13:435-441; Matsuda and Mori, 1997, Zoolog.Sci. 14:159-165).

[0005] The cellular environment in which a receptor is expressed mayinfluence the biological response exhibited upon binding of a ligand tothe receptor. Thus, for example, when a neuronal cell expressing a Trkreceptor is exposed to a neurotrophin which binds that receptor,neuronal survival and differentiation results. When the same receptor isexpressed by a fibroblast, exposure to the neurotrophin results inproliferation of the fibroblast (Glass, et al., 1991, Cell 66:405-413).Thus, it appears that the extracellular domain provides the determiningfactor as to the ligand specificity, and once signal transduction isinitiated the cellular environment will determine the phenotypic outcomeof that signal transduction.

[0006] Comparison of the rat PRL receptor sequence with that of themammalian GH receptor sequence has demonstrated some regions of identitybetween the two receptors, suggesting that the receptors originate froma common ancestry and may actually belong to a larger family ofreceptors, all of which share certain sequence homologies and perhapsrelated biological function. Because ligands and their receptors appearto mediate a number of important biological functions during development(e.g., bone growth, sexual maturation) as well as in the adult (e.g.,homeostasis, reproduction), the identification and isolation of novelreceptors may be used as a means of identifying new ligands or to studyintracellular signalling pathways that may play a crucial role duringdevelopment and in the maintenance of the adult phenotype. Often suchnovel receptors are identified and isolated by searching for additionalmembers of known families of receptors using, for example, PCR-basedscreens involving known regions of homology among receptor familymembers. (See, for example, Maisonpierre, et al., 1993, Oncogene8:1631-1637). Isolation of such so called “orphan” receptors, for whichno ligand is known, and subsequent determination of the tissues in whichsuch receptors are expressed, provides insight into the regulation ofthe development, differentiation, growth, proliferation, survival andregeneration of cells in target tissues. Further, such receptors may beused to isolate their cognate ligand, which may then be used to regulatethe development, differentiation, growth, proliferation, survival andregeneration of cells expressing the receptor.

SUMMARY OF THE INVENTION

[0007] The present invention provides for a novel mammalian receptor,termed orphan cytokine receptor-1 (OCR1), which is expressed at highlevels in heart, brain, placenta, skeletal muscle, and pancreas, and atmoderate levels in lung, prostate, testis, uterus, small intestine andcolon. Specifically, the present invention provides for a novel humanreceptor termed HUMAN OCR1. The present invention further provides for anovel mouse receptor termed MOUSE OCR1. Throughout this description,reference to MAMMALIAN OCR1 includes, but is not limited to, thespecific embodiments of HUMAN OCR1 and MOUSE OCR1 as described herein.The protein appears to be related to the cytokine family of receptorswhich includes, but is not limited to, the prolactin/growth hormonereceptors. The present invention further provides for an isolatednucleic acid molecule encoding MAMMALIAN OCR1.

[0008] The present invention also provides for a protein or polypeptidethat comprises the extracellular domain of MAMMALIAN OCR1 and thenucleic acid which encodes such extracellular domain.

[0009] The invention further provides for vectors comprising an isolatednucleic acid molecule encoding MAMMALIAN OCR1 or its extracellulardomain, which can be used to express MAMMALIAN OCR1 in bacteria, yeast,insect or mammalian cells.

[0010] The present invention further provides for use of the MAMMALIANOCR1 receptor or its extracellular or intracellular domain in screeningfor drugs that interact with MAMMALIAN OCR1. Novel agents that bind tothe receptor(s) described herein may mediate survival anddifferentiation in cells naturally expressing the receptor, but also mayconfer survival and proliferation when used to treat cells engineered toexpress the receptor. In particular embodiments, the extracellulardomain (soluble receptor) of MAMMALIAN OCR1 is utilized in screens forcognate ligands.

[0011] The invention also provides for a nucleic acid probe capable ofhybridizing with a sequence included within the nucleic acid sequenceencoding MAMMALIAN OCR1 useful for the detection of MAMMALIAN OCR1expressing tissue in humans and animals.

[0012] The invention further provides for antibodies directed againstMAMMALIAN OCR1.

[0013] The present invention also has diagnostic and therapeuticutilities. In particular embodiments of the invention, methods ofdetecting aberrancies in the function or expression of the receptordescribed herein may be used in the diagnosis of endocrine or otherdisorders. In other embodiments, manipulation of the receptor oragonists which bind this receptor may be used in the treatment of, forexample, endocrine disorders. In further embodiments, the extracellulardomain of the receptor is utilized as a blocking agent which blocks thebinding of ligand to target cells.

[0014] In a further embodiment of the invention, patients that sufferfrom an excess of HUMAN OCR1 may be treated by administering aneffective amount of anti-sense RNA or anti-senseoligodeoxyribonucleotides corresponding to the HUMAN OCR1 gene codingregion, thereby decreasing expression of HUMAN OCR1.

DETAILED DESCRIPTION OF THE INVENTION

[0015] The invention provides MAMMALIAN OCR1 polypeptides which includeisolated MAMMALIAN OCR1 polypeptides and recombinant polypeptidescomprising a MAMMALIAN OCR1 amino acid sequence, or a functionalMAMMALIAN OCR1 polypeptide domain thereof having an assay-discernableMAMMALIAN OCR1-specific activity. Accordingly, the polypeptides may bedeletion mutants of the disclosed MAMMALIAN OCR1 polypeptide and may beprovided as fusion products, e.g., with non-MAMMALIAN OCR1 polypeptides.The subject MAMMALIAN OCRI polypeptides have MAMMALIAN OCR1-specificactivity or function.

[0016] A number of applications for MAMMALIAN OCR1 polypeptides aresuggested from their properties. MAMMALIAN OCR1 polypeptides may beuseful in the study and treatment of conditions similar to those whichare treated using cytokines and/or hormones. Furthermore, the MAMMALIANOCR1 cDNA may be useful as a diagnostic tool, such as through the use ofoligonucleotides as primers in a PCR test to amplify those sequenceshaving similarities to the oligonucleotide primer, and to see how muchMAMMALIAN OCR1 mRNA is present in a particular tissue or sample. Theisolation of MAMMALIAN OCR1, of course, also provides the key to isolateits putative ligand, other MAMMALIAN OCR1 binding polypeptides, and/orstudy its properties.

[0017] MAMMALIAN OCR1-specific activity or function may be determined byconvenient in vitro, cell based or in vivo assays. In vitro or cellbased assays include but are not limited to binding assays and cellculture assays. In vivo assays include but are not limited to immuneresponse, gene therapy and transgenic animals. Binding assays encompassany assay where the specific molecular interaction of a MAMMALIAN OCR1polypeptide with a binding target is evaluated. The binding target maybe a natural binding target, or a nonnatural binding target such as aspecific immune polypeptide such as an antibody, or a MAMMALIANOCR1-specific binding agent.

[0018] The claimed MAMMALIAN OCR1 polypeptides may be isolated orpure—an “isolated” polypeptide is one that is no longer accompanied bysome of the material with which it is associated in its natural state,and that preferably constitutes at least about 0.5%, and more preferablyat least about 5% by weight of the total polypeptide in a given sample;a “pure” polypeptide constitutes at least about 90%, and preferably atleast about 99% by weight of the total polypeptide in a given sample.The subject polypeptides may be synthesized, produced by recombinanttechnology, or purified from cells. A wide variety of molecular andbiochemical methods are available for biochemical synthesis, molecularexpression and purification of the subject compositions, see e.g.,Molecular Cloning, A Laboratory Manual (Sambrook, et al., Cold SpringHarbor Laboratory, Cold Spring Harbor, N.Y.), Current Protocols inMolecular Biology (Eds. Ausubel, et al., Greene Publ. Assoc.,Wiley-Interscience, NY).

[0019] The subject polypeptides find a wide variety of uses includingbut not limited to use as immunogens, targets in screening assays,bioactive reagents for modulating cell growth, differentiation and/orfunction. For example, the invention provides methods for modifying thephysiology of a cell comprising contacting the extracellular surface ofthe cell or medium surrounding the cell with an exogenous MAMMALIAN OCR1polypeptide under conditions whereby the added polypeptide specificallyinteracts with a component of the medium and/or the extracellularsurface to effect a change in the physiology of the cell. According tothese methods, the extracellular surface includes plasmamembrane-associated molecules. The term “exogenous MAMMALIAN OCR1polypeptide” refers to polypeptides not made by the cell or, if so,expressed at non-natural levels, times or physiologic locales. Media,include, but are not limited to, in vitro culture media and/orphysiological fluids such as blood, synovial fluid and lymph. Thepolypeptides may be introduced, expressed, or repressed in specificpopulations of cells by any convenient way, including but not limitedto, microinjection, promoter-specific expression of recombinant proteinor targeted delivery of lipid vesicles.

[0020] The invention provides MAMMALIAN OCR1-specific binding agents,methods of identifying and making such agents, and their use indiagnosis, therapy and pharmaceutical development. MAMMALIANOCR1-specific binding agents include MAMMALIAN OCR1-specific antibodies(See, e.g., Harlow and Lane (1988) Antibodies, A Laboratory Manual, ColdSpring Harbor Laboratory, Cold Spring Harbor, N.Y.) and also includesother binding agents identified with assays such as one-, two- andthree-hybrid screens, and non-natural binding agents identified inscreens of chemical libraries such as described below. Agents ofparticular interest modulate MAMMALIAN OCR1 polypeptide function.

[0021] The invention further provides for the production of secretedpolypeptides consisting of the entire extracellular domain of MAMMALIANOCR-1 fused to the human immunoglobulin gamma-1 constant region (IgG1constant) or the human immunoglobulin gamma-1 Fc region (IgG1 Fc). Thisfusion polypeptide is called a MAMMALIAN OCRA1 “receptorbody” (RB), andwould be normally expected to exist as a dimer in solution based onformation of disulfide linkages between individual IgG1 constant regionor IgG1 Fc region tails. MAMMALIAN OCR1 RB encoding nucleic acids may bepart of expression vectors and may be incorporated into recombinant hostcells, e.g., for expression and screening, for transgenic animals, orfor functional studies such as the efficacy of candidate drugs fordiseases associated with MAMMALIAN OCR1 polypeptide-mediated signaltransduction. Expression systems are selected and/or tailored to effectMAMMALIAN OCR1 RB polypeptide structural and functional variants throughalternative post-translational processing.

[0022] The invention provides MAMMALIAN OCR1 nucleic acids, which find awide variety of applications, including but not limited to, use astranslatable transcripts, hybridization probes, PCR primers, ordiagnostic nucleic acids, as well as use in detecting the presence ofMAMMALIAN OCR1 genes and gene transcripts and in detecting or amplifyingnucleic acids encoding additional MAMMALIAN OCR1 homologs and structuralanalogs.

[0023] The subject nucleic acids are of synthetic/non-natural sequencesand/or are isolated, i.e., no longer accompanied by some of the materialwith which it is associated in its natural state, preferablyconstituting at least about 0.5%, more preferably at least about 5% byweight of total nucleic acid present in a given fraction, and usuallyrecombinant, meaning they comprise a non-natural sequence or a naturalsequence joined to a nucleotide(s) other than that to which it is joinedon a natural chromosome. Nucleic acids comprising the nucleotidesequence disclosed herein and fragments thereof, contain such sequenceor fragment at a terminus, immediately flanked by a sequence other thanthat to which it is joined on a natural chromosome, or flanked by anative flanking region fewer than 10 kb, preferably fewer than 2 kb,which is immediately flanked by a sequence other than that to which itis joined on a natural chromosome. While the nucleic acids are usuallyRNA or DNA, it is often advantageous to use nucleic acids comprisingother bases or nucleotide analogs to provide, example, modifiedstability.

[0024] The sequence of the disclosed MAMMALIAN OCR1 nucleic acid is usedto obtain the deduced MAMMALIAN OCR1 polypeptide sequence. Further, thesequence of the disclosed MAMMALIAN OCR1 nucleic acid is optimized forselected expression systems (Holler, et al., (1993) Gene 136:323-328;Martin, et al., (1995) Gene 154:150-166) or used to generate degenerateoligonucleotide primers and probes for use in the isolation of naturalMAMMALIAN OCR1 encoding nucleic acid sequences (“GCG” software, GeneticsComputer Group, Inc., Madison, Wis.). MAMMALIAN OCR1 encoding nucleicacids may be part of expression vectors and may be incorporated intorecombinant host cells, e.g., for expression and screening, fortransgenic animals, or for functional studies such as the efficacy ofcandidate drugs for diseases associated with MAMMALIAN OCR1polypeptide-mediated signal transduction. Expression systems areselected and/or tailored to effect MAMMALIAN OCR1 polypeptide structuraland functional variants through alternative post-translationalprocessing.

[0025] The invention also provides for nucleic acid hybridization probesand replication/amplification primers having a MAMMALIAN OCR1cDNA-specific sequence and sufficient to effect specific hybridizationwith SEQ. NO. 1 or SEQ. NO. 3. Demonstrating specific hybridizationgenerally requires stringent conditions, for example, hybridizing in abuffer comprising 30% formamide in 5×SSPE (0.18 M NaCl, 0.01 M NaPO₄, pH7.7, 0.001 M EDTA) buffer at a temperature of 42° C. and remaining boundwhen subject to washing at 42° C. with 0.2×SSPE; preferably hybridizingin a buffer comprising 50% formamide in 5×SSPE buffer at a temperatureof 42° C. and remaining bound when subject to washing at 42° C. with0.2×SSPE buffer at 42° C. MAMMALIAN OCR1 cDNA homologs can also bedistinguished from one another using alignment algorithms, such asBLASTX (Altschul, et al., (1990) Basic Local Alignment Search Tool, J.Mol. Biol. 215:403-410).

[0026] MAMMALIAN OCR1 hybridization probes find use in identifyingwild-type and mutant alleles in clinical and laboratory samples. Mutantalleles are used to generate allele-specific oligonucleotide (ASO)probes for high-throughput clinical diagnoses. MAMMALIAN OCR1 nucleicacids are also used to modulate cellular expression or intracellularconcentration or availability of active MAMMALIAN OCR1 polypeptides.MAMMALIAN OCR1 inhibitory nucleic acids are typically antisense- singlestranded sequences comprising complements of the disclosed MAMMALIANOCR1 coding sequences. Antisense modulation of the expression of a givenMAMMALIAN OCR1 polypeptide may employ antisense nucleic acids operablylinked to gene regulatory sequences. Cells are transfected with a vectorcomprising a MAMMALIAN OCR1 sequence with a promoter sequence orientedsuch that transcription of the gene yields an antisense transcriptcapable of binding to endogenous MAMMALIAN OCR1 encoding mRNA.Transcription of the antisense nucleic acid may be constitutive orinducible and the vector may provide for stable extrachromosomalmaintenance or integration. Alternatively, single-stranded antisensenucleic acids that bind to genomic DNA or mRNA encoding a givenMAMMALIAN OCR1 polypeptide may be administered to the target cell, in ortemporarily isolated from a host, at a concentration that results in asubstantial reduction in expression of the targeted polypeptide. Anenhancement in MAMMALIAN OCR1 expression is effected by introducing intothe targeted cell type MAMMALIAN OCR1 nucleic acids which increase thefunctional expression of the corresponding gene products. Such nucleicacids may be MAMMALIAN OCR1 expression vectors, vectors which upregulatethe functional expression of an endogenous allele, or replacementvectors for targeted correction of mutant alleles. Techniques forintroducing the nucleic acids into viable cells are known in the art andinclude, but are not limited to, retroviral-based transfection or viralcoat protein-liposome mediated transfection.

[0027] The invention provides efficient methods of identifying agents,compounds or lead compounds for agents active at the level of MAMMALIANOCR1 modulatable cellular function. Generally, these screening methodsinvolve assaying for compounds which modulate the interaction ofMAMMALIAN OCR1 with a natural MAMMALIAN OCR1 binding target. A widevariety of assays for binding agents are provided including, but notlimited to, protein-protein binding assays, immunoassays, or cell basedassays. Preferred methods are amenable to automated, cost-effective,high throughput screening of chemical libraries for lead compounds.

[0028] In vitro binding assays employ a mixture of components includinga MAMMALIAN OCR1 polypeptide, which may be part of a fusion product withanother peptide or polypeptide, e.g., a tag for detection or anchoring.The assay mixtures comprise a natural MAMMALIAN OCR1 binding target.While native binding targets may be used, it is frequently preferred touse portions thereof as long as the portion provides binding affinityand avidity to the subject MAMMALIAN OCR1 conveniently measurable in theassay. The assay mixture also comprises a candidate pharmacologicalagent. Candidate agents encompass numerous chemical classes, thoughtypically they are organic compounds, preferably small organiccompounds, and are obtained from a wide variety of sources includinglibraries of synthetic or natural compounds. A variety of other reagentssuch as salts, buffers, neutral proteins, e.g., albumin, detergents,protease inhibitors, nuclease inhibitors, or antimicrobial agents mayalso be included. The mixture components can be added in any order thatprovides for the requisite bindings and incubations may be performed atany temperature which facilitates optimal binding. The mixture isincubated under conditions whereby, but for the presence of thecandidate pharmacological agent, the MAMMALIAN OCR1 polypeptidespecifically binds the binding target, portion or analog with areference binding affinity. Incubation periods are chosen for optimalbinding but are also minimized to facilitate rapid, high throughputscreening.

[0029] After incubation, the agent-biased binding between the MAMMALIANOCR1 polypeptide and one or more binding targets is detected by anyconvenient way. For cell-free binding type assays, a separation step isoften used to separate bound from unbound components. Separation may beeffected by any number of methods that include, but are not limited to,precipitation or immobilization followed by washing by, e.g., membranefiltration or gel chromatography. For cell-free binding assays, one ofthe components usually comprises or is coupled to a label. The label mayprovide for direct detection as radioactivity, luminescence, optical orelectron density, or indirect detection such as an epitope tag or anenzyme. A variety of methods may be used to detect the label dependingon the nature of the label and other assay components, including but notlimited to, through optical or electron density, radiative emissions,nonradiative energy transfers, or indirectly detected with, as anonlimiting example, antibody conjugates. A difference in the bindingaffinity of the MAMMALIAN OCR1 polypeptide to the target in the absenceof the agent as compared with the binding affinity in the presence ofthe agent indicates that the agent modulates the binding of theMAMMALIAN OCR1 polypeptide to the corresponding binding target. Adifference, as used herein, is statistically significant and preferablyrepresents at least a 50%, more preferably at least a 90% difference.

[0030] The invention provides for a method for modifying the physiologyof a cell comprising an extracellular surface in contact with a medium,said method comprising the step of contacting said medium with anexogenous MAMMALIAN OCR1 polypeptide under conditions whereby saidpolypeptide specifically interacts with at least one of the componentsof said medium to effect a change in the physiology of said cell.

[0031] The invention further provides for a method for screening forbiologically active agents, said method comprising the steps of a)incubating a MAMMALIAN OCR1 polypeptide in the presence of a MAMMALIANOCR1 polypeptide-specific binding target and a candidate agent, underconditions whereby, but for the presence of said agent, said polypeptidespecifically binds said binding target at a reference affinity; b)detecting the binding affinity of said polypeptide to said bindingtarget to determine an agent-biased affinity, wherein a differencebetween the agent-biased affinity and the reference affinity indicatesthat said agent modulates the binding of said polypeptide to saidbinding target.

[0032] One embodiment of the invention is an isolated MAMMALIAN OCR1polypeptide comprising the amino acid sequence as set forth herein or afragment thereof having MAMMALIAN OCR1-specific activity.

[0033] Another embodiment of the invention is a recombinant nucleic acidencoding MAMMALIAN OCR1 polypeptide comprising the amino acid sequenceas set forth herein or a fragment thereof having MAMMALIAN OCR1-specificactivity.

[0034] Still another embodiment is an isolated nucleic acid comprising anucleotide sequence as set forth herein in SEQ. NO. 3 or a fragmentthereof having at least 18 consecutive bases and which can specificallyhybridize with a nucleic acid having the sequence of native MAMMALIANOCR1.

[0035] The present invention also provides for antibodies to theMAMMALIAN OCR1 polypeptides described herein which are useful fordetection of the polypeptides in, for example, diagnostic applications.For preparation of monoclonal antibodies directed toward MAMMALIAN OCR1polypeptides, any technique which provides for the production ofantibody molecules by continuous cell lines in culture may be used. Forexample, the hybridoma technique originally developed by Kohler andMilstein (1975, Nature 256:495-497), as well as the trioma technique,the human B-cell hybridoma technique (Kozbor et al., 1983, ImmunologyToday 4:72), and the EBV-hybridoma technique to produce human monoclonalantibodies (Cole et al., 1985, in “Monoclonal Antibodies and CancerTherapy”, Alan R. Liss, Inc. pp. 77-96) and the like are within thescope of the present invention.

[0036] The monoclonal antibodies for diagnostic or therapeutic use maybe human monoclonal antibodies or chimeric human-mouse (or otherspecies) monoclonal antibodies. Human monoclonal antibodies may be madeby any of numerous techniques known in the art (e.g., Teng et al., 1983,Proc. Natl. Acad. Sci. U.S.A. 80:7308-7312; Kozbor et al., 1983,Immunology Today 4:72-79; Olsson et al., 1982, Meth. Enzymol. 92:3-16).Chimeric antibody molecules may be prepared containing a mouseantigen-binding domain with human constant regions (Morrison et al.,1984, Proc. Natl. Acad. Sci. U.S.A. 81:6851, Takeda et al., 1985, Nature314:452).

[0037] Various procedures known in the art may be used for theproduction of polyclonal antibodies to the MAMMALIAN OCR1 polypeptidesdescribed herein. For the production of antibody, various host animalscan be immunized by injection with the MAMMALIAN OCR1 polypeptides, orfragments or derivatives thereof, including but not limited to rabbits,mice and rats. Various adjuvants may be used to increase theimmunological response, depending on the host species, including but notlimited to Freund's (complete and incomplete), mineral gels such asaluminum hydroxide, surface active substances such as lysolecithin,pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpethemocyanins, dinitrophenol, and potentially useful human adjuvants suchas BCG (Bacille Calmette-Guerin) and Corynebacterium parvum.

[0038] A molecular clone of an antibody to a selected MAMMALIAN OCR1polypeptide epitope can be prepared by known techniques. Recombinant DNAmethodology (see e.g., Maniatis et al., 1982, Molecular Cloning, ALaboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor,N.Y.) may be used to construct nucleic acid sequences which encode amonoclonal antibody molecule, or antigen binding region thereof.

[0039] The present invention provides for antibody molecules as well asfragments of such antibody molecules. Antibody fragments which containthe idiotype of the molecule can be generated by known techniques. Forexample, such fragments include, but are not limited to, the F(ab′)₂fragment which can be produced by pepsin digestion of the antibody theFab′ fragments which can be generated by reducing the disulfide bridgesof the F(ab′)₂ fragment, and the Fab fragments which can be generated bytreating the antibody molecule with papain and a reducing agent.Antibody molecules may be purified by known techniques including, butnot limited to, immunoabsorption or immunoaffinity chromatography,chromatographic methods such as HPLC (high performance liquidchromatography), or a combination thereof.

[0040] The following example is offered by way of illustration and notby way of limitation.

EXAMPLE 1 Cloning and Sequencing of Nucleic Acid Encoding MOUSE OCR-1

[0041] Amino acid sequences of known human and mouse members of thecytokine receptor family were used as tblastn queries to search the NIHEST database of random fragments of mRNA sequences (Altschul et al.,(1990), Basic local alignment search tool J. Mol. Biol. 215:403-10).Each query generated a list of hits, i.e. EST sequences with asubstantial sequence similarity to the query sequence. Typically, thehits on top of the list corresponded to mRNA copies of the queryprotein, followed by ESTs derived from other members of the family andrandom-chance similarities.

[0042] A parser program was used to combine and sort all the hits fromsearches with all the members of the family. This allowed rapidsubtraction of all the hits corresponding to known proteins. Theremaining hits were analyzed for conservation of sequence motifscharacteristic for the family. Additional database searches wereperformed to identify overlapping ESTs. Two cDNA clone(s) from theI.M.A.G.E. consortium were discerned to contain homologous sequence.Clone #387741 (the '741 clone) (GeneBank Accession No. W66776) and clone#479043 (the '043 clone) (GeneBank Accession No. AA049280) were obtainedfrom Research Genetics, Inc. (Huntsville, Ala.) and sequenced using theABI 373A DNA sequencer and Taq Dideoxy Terminator Cycle Sequencing Kit(Applied Biosystems, Inc., Foster City, Calif.).

[0043] The '043 clone contained a partial sequence of MOUSE OCR1 andclone '741 contained a 1215 bp nucleotide sequence (SEQ. NO. 1) thattranslated into a full length single coding frame encoding a 406 aminoacid protein (SEQ. NO. 2) designated MOUSE OCR1 as set forth below.MOUSE OCR1 revealed sequence similarity to members of the cytokinereceptor family.

EXAMPLE 2 Cloning and Sequencing of Nucleic Acid Encoding HUMAN OCR1

[0044] Amino acid sequences of known human and mouse members of thecytokine receptor family were used as tblastn queries to search the NIHEST database of random fragments of mRNA sequences (Altschul et al.,(1990), Basic local alignment search tool J. Mol. Biol. 215:403-10).Each query generated a list of hits, i.e. EST sequences with asubstantial sequence similarity to the query sequence. Typically, thehits on top of the list corresponded to mRNA copies of the queryprotein, followed by ESTs derived from other members of the family andrandom-chance similarities.

[0045] A parser program was used to combine and sort all the hits fromsearches with all the members of the family. This allowed rapidsubtraction of all the hits corresponding to known proteins. Theremaining hits were analyzed for conservation of sequence motifscharacteristic for the family. Additional database searches wereperformed to identify overlapping ESTs. Three cDNA clones from theI.M.A.G.E. consortium were discerned to contain homologous sequence.Clone #324067 (the '067 clone) (GeneBank Accession No. W466040), clone#490004 (the '004 clone) (GeneBank Accession No. AA127694), and clone#302666 (the '666 clone) (GeneBank Accession No. W37175). All three wereobtained from Genome Systems Inc. (St. Louis, Mo.) and sequenced usingthe ABI 373A DNA sequencer and Taq Dideoxy Terminator Cycle SequencingKit (Applied Biosystems, Inc., Foster City, Calif.).

[0046] Both the '004 clone and the '067 clone contained partial sequenceand the '666 clone contained a 1302 bp nucleotide sequence (SEQ. NO. 3)that translated into a full length single coding frame encoding a 435amino acid protein (SEQ. NO. 4) designated HUMAN OCR1 as set forthbelow. HUMAN OCR1 revealed sequence similarity to members of thecytokine receptor family.

[0047] The present invention is not to be limited in scope by thespecific embodiments described herein. Indeed, various modifications ofthe invention in addition to those described herein will become apparentto those skilled in the art from the foregoing description andaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

1 4 1 1218 DNA MOUSE CDS (1)..(1215) 1 tcc tcg ctg tgg tcg cct ctg ttgctc tgt gtc ctc ggg gtg cct cgg 48 Ser Ser Leu Trp Ser Pro Leu Leu LeuCys Val Leu Gly Val Pro Arg 1 5 10 15 ggc gga tcg gga gcc cac aca gctgta atc agc ccc cag gac ccc acc 96 Gly Gly Ser Gly Ala His Thr Ala ValIle Ser Pro Gln Asp Pro Thr 20 25 30 ctt ctc atc ggc tcc tcc ctg caa gctacc tgc tct ata cat gga gac 144 Leu Leu Ile Gly Ser Ser Leu Gln Ala ThrCys Ser Ile His Gly Asp 35 40 45 aca cct ggg gcc acc gct gag ggg ctc tactgg acc ctc aat ggt cgc 192 Thr Pro Gly Ala Thr Ala Glu Gly Leu Tyr TrpThr Leu Asn Gly Arg 50 55 60 cgc ctg ccc tct gag ctg tcc cgc ctc ctt aacacc tcc acc ctg gcc 240 Arg Leu Pro Ser Glu Leu Ser Arg Leu Leu Asn ThrSer Thr Leu Ala 65 70 75 80 ctg gcc ctg gct aac ctt aat ggg tcc agg cagcag tca gga gac aat 288 Leu Ala Leu Ala Asn Leu Asn Gly Ser Arg Gln GlnSer Gly Asp Asn 85 90 95 ctg gtg tgt cac gcc cga gat ggc agc att ctg gctggc tcc tgc ctc 336 Leu Val Cys His Ala Arg Asp Gly Ser Ile Leu Ala GlySer Cys Leu 100 105 110 tat gtt ggc ttg ccc cct gag aag cct ttt aac atcagc tgc tgg tcc 384 Tyr Val Gly Leu Pro Pro Glu Lys Pro Phe Asn Ile SerCys Trp Ser 115 120 125 cgg aac atg aag gat ctc acg tgc cgc tgg aca ccgggt gca cac ggg 432 Arg Asn Met Lys Asp Leu Thr Cys Arg Trp Thr Pro GlyAla His Gly 130 135 140 gag aca ttc tta cat acc aac tac tcc ctc aag tacaag ctg agg tgg 480 Glu Thr Phe Leu His Thr Asn Tyr Ser Leu Lys Tyr LysLeu Arg Trp 145 150 155 160 tac ggt cag gat aac aca tgt gag gag tac cacact gtg ggc cct cac 528 Tyr Gly Gln Asp Asn Thr Cys Glu Glu Tyr His ThrVal Gly Pro His 165 170 175 tca tgc cat atc ccc aag gac ctg gcc ctc ttcact ccc tat gag atc 576 Ser Cys His Ile Pro Lys Asp Leu Ala Leu Phe ThrPro Tyr Glu Ile 180 185 190 tgg gtg gaa gcc acc aat cgc cta ggc tca gcaaga tct gat gtc ctc 624 Trp Val Glu Ala Thr Asn Arg Leu Gly Ser Ala ArgSer Asp Val Leu 195 200 205 aca ctg gat gtc ctg gac gtg gtg acc acg gacccc cca ccc gac gtg 672 Thr Leu Asp Val Leu Asp Val Val Thr Thr Asp ProPro Pro Asp Val 210 215 220 cac gtg agc cgc gtt ggg ggc ctg gag gac cagctg agt gtg cgc tgg 720 His Val Ser Arg Val Gly Gly Leu Glu Asp Gln LeuSer Val Arg Trp 225 230 235 240 gtc tca cca cca gct ctc aag gat ttc ctcttc caa gcc aag tac cag 768 Val Ser Pro Pro Ala Leu Lys Asp Phe Leu PheGln Ala Lys Tyr Gln 245 250 255 atc cgc tac cgc gtg gag gac agc gtg gactgg aag gtg gtg gat gac 816 Ile Arg Tyr Arg Val Glu Asp Ser Val Asp TrpLys Val Val Asp Asp 260 265 270 gtc agc aac cag acc tcc tgc cgt ctc gcgggc ctg aag ccc ggc acc 864 Val Ser Asn Gln Thr Ser Cys Arg Leu Ala GlyLeu Lys Pro Gly Thr 275 280 285 gtt tac ttc gtc caa gtg cgt tgt aac ccattc ggg atc tat ggg tcg 912 Val Tyr Phe Val Gln Val Arg Cys Asn Pro PheGly Ile Tyr Gly Ser 290 295 300 aaa aag gcg gga atc tgg agc gag tgg agccac ccc acc gct gcc tcc 960 Lys Lys Ala Gly Ile Trp Ser Glu Trp Ser HisPro Thr Ala Ala Ser 305 310 315 320 acc cct cga agt gag cgc ccg ggc ccgggc ggc ggg gtg tgc gag ccg 1008 Thr Pro Arg Ser Glu Arg Pro Gly Pro GlyGly Gly Val Cys Glu Pro 325 330 335 cgg ggc ggc gag ccc agc tcg ggc ccggtg cgg cgc gag ctc aag cag 1056 Arg Gly Gly Glu Pro Ser Ser Gly Pro ValArg Arg Glu Leu Lys Gln 340 345 350 ttc ctc ggc tgg ctc aag aag cac gcatac tgc tcg aac ctt agt ttc 1104 Phe Leu Gly Trp Leu Lys Lys His Ala TyrCys Ser Asn Leu Ser Phe 355 360 365 cgc ctg tac gac cag tgg cgt gct tggatg cag aag tca cac aag acc 1152 Arg Leu Tyr Asp Gln Trp Arg Ala Trp MetGln Lys Ser His Lys Thr 370 375 380 cga aac cag gac gag ggg atc ctg ccctcg ggc aga cgg ggt gcg gcg 1200 Arg Asn Gln Asp Glu Gly Ile Leu Pro SerGly Arg Arg Gly Ala Ala 385 390 395 400 aga ggt cct gcc ggc taa 1218 ArgGly Pro Ala Gly 405 2 405 PRT MOUSE 2 Ser Ser Leu Trp Ser Pro Leu LeuLeu Cys Val Leu Gly Val Pro Arg 1 5 10 15 Gly Gly Ser Gly Ala His ThrAla Val Ile Ser Pro Gln Asp Pro Thr 20 25 30 Leu Leu Ile Gly Ser Ser LeuGln Ala Thr Cys Ser Ile His Gly Asp 35 40 45 Thr Pro Gly Ala Thr Ala GluGly Leu Tyr Trp Thr Leu Asn Gly Arg 50 55 60 Arg Leu Pro Ser Glu Leu SerArg Leu Leu Asn Thr Ser Thr Leu Ala 65 70 75 80 Leu Ala Leu Ala Asn LeuAsn Gly Ser Arg Gln Gln Ser Gly Asp Asn 85 90 95 Leu Val Cys His Ala ArgAsp Gly Ser Ile Leu Ala Gly Ser Cys Leu 100 105 110 Tyr Val Gly Leu ProPro Glu Lys Pro Phe Asn Ile Ser Cys Trp Ser 115 120 125 Arg Asn Met LysAsp Leu Thr Cys Arg Trp Thr Pro Gly Ala His Gly 130 135 140 Glu Thr PheLeu His Thr Asn Tyr Ser Leu Lys Tyr Lys Leu Arg Trp 145 150 155 160 TyrGly Gln Asp Asn Thr Cys Glu Glu Tyr His Thr Val Gly Pro His 165 170 175Ser Cys His Ile Pro Lys Asp Leu Ala Leu Phe Thr Pro Tyr Glu Ile 180 185190 Trp Val Glu Ala Thr Asn Arg Leu Gly Ser Ala Arg Ser Asp Val Leu 195200 205 Thr Leu Asp Val Leu Asp Val Val Thr Thr Asp Pro Pro Pro Asp Val210 215 220 His Val Ser Arg Val Gly Gly Leu Glu Asp Gln Leu Ser Val ArgTrp 225 230 235 240 Val Ser Pro Pro Ala Leu Lys Asp Phe Leu Phe Gln AlaLys Tyr Gln 245 250 255 Ile Arg Tyr Arg Val Glu Asp Ser Val Asp Trp LysVal Val Asp Asp 260 265 270 Val Ser Asn Gln Thr Ser Cys Arg Leu Ala GlyLeu Lys Pro Gly Thr 275 280 285 Val Tyr Phe Val Gln Val Arg Cys Asn ProPhe Gly Ile Tyr Gly Ser 290 295 300 Lys Lys Ala Gly Ile Trp Ser Glu TrpSer His Pro Thr Ala Ala Ser 305 310 315 320 Thr Pro Arg Ser Glu Arg ProGly Pro Gly Gly Gly Val Cys Glu Pro 325 330 335 Arg Gly Gly Glu Pro SerSer Gly Pro Val Arg Arg Glu Leu Lys Gln 340 345 350 Phe Leu Gly Trp LeuLys Lys His Ala Tyr Cys Ser Asn Leu Ser Phe 355 360 365 Arg Leu Tyr AspGln Trp Arg Ala Trp Met Gln Lys Ser His Lys Thr 370 375 380 Arg Asn GlnAsp Glu Gly Ile Leu Pro Ser Gly Arg Arg Gly Ala Ala 385 390 395 400 ArgGly Pro Ala Gly 405 3 1305 DNA HUMAN CDS (1)..(1302) 3 cgg ccg ccg ccgttg ctg ccc ctg ctg ctg ctg ctc tgc gtc ctc ggg 48 Arg Pro Pro Pro LeuLeu Pro Leu Leu Leu Leu Leu Cys Val Leu Gly 1 5 10 15 gcg ccg cga gccgga tca gga gcc cac aca gct gtg atc agt ccc cag 96 Ala Pro Arg Ala GlySer Gly Ala His Thr Ala Val Ile Ser Pro Gln 20 25 30 gat ccc acg ctt ctcatc ggc tcc tcc ctg ctg gcc acc tgc tca gtg 144 Asp Pro Thr Leu Leu IleGly Ser Ser Leu Leu Ala Thr Cys Ser Val 35 40 45 cac gga gac cca cca ggagcc acc gcc gag ggc ctc tac tgg acc ctc 192 His Gly Asp Pro Pro Gly AlaThr Ala Glu Gly Leu Tyr Trp Thr Leu 50 55 60 aac ggg cgc cgc ctg ccc cctgag ctc tcc cgt gta ctc aac gcc tcc 240 Asn Gly Arg Arg Leu Pro Pro GluLeu Ser Arg Val Leu Asn Ala Ser 65 70 75 80 acc ttg gct ctg gcc ctg gccaac ctc aat ggg tcc agg cag cgg tcg 288 Thr Leu Ala Leu Ala Leu Ala AsnLeu Asn Gly Ser Arg Gln Arg Ser 85 90 95 ggg gac aac ctc gtg tgc cac gcccgt gac ggc agc atc ctg gct ggc 336 Gly Asp Asn Leu Val Cys His Ala ArgAsp Gly Ser Ile Leu Ala Gly 100 105 110 tcc tgc ctc tat gtt ggc ctg ccccca gag aaa ccc gtc aac atc agc 384 Ser Cys Leu Tyr Val Gly Leu Pro ProGlu Lys Pro Val Asn Ile Ser 115 120 125 tgc tgg tcc aag aac atg aag gacttg acc tgc cgc tgg acg cca ggg 432 Cys Trp Ser Lys Asn Met Lys Asp LeuThr Cys Arg Trp Thr Pro Gly 130 135 140 gcc cac ggg gag acc ttc ctc cacacc aac tac tcc ctc aag tac aag 480 Ala His Gly Glu Thr Phe Leu His ThrAsn Tyr Ser Leu Lys Tyr Lys 145 150 155 160 ctt agg tgg tat ggc cag gacaac aca tgt gag gag tac cac aca gtg 528 Leu Arg Trp Tyr Gly Gln Asp AsnThr Cys Glu Glu Tyr His Thr Val 165 170 175 ggg ccc cac tcc tgc cac atcccc aag gac ctg gct ctc ttt acg ccc 576 Gly Pro His Ser Cys His Ile ProLys Asp Leu Ala Leu Phe Thr Pro 180 185 190 tat gag atc tgg gtg gag gccacc aac cgc ctg ggc tct gcc cgc tcc 624 Tyr Glu Ile Trp Val Glu Ala ThrAsn Arg Leu Gly Ser Ala Arg Ser 195 200 205 gat gta ctc acg ctg gat atcctg gat gtg ggg tcc cac ctg ccc ctc 672 Asp Val Leu Thr Leu Asp Ile LeuAsp Val Gly Ser His Leu Pro Leu 210 215 220 ccc agc ccg gca act ccc gggttg tcc ctg ctg gtc aga ggg aag gta 720 Pro Ser Pro Ala Thr Pro Gly LeuSer Leu Leu Val Arg Gly Lys Val 225 230 235 240 gtg acc acg gac ccc ccgccc gac gtg cac gtg agc cgc gtc ggg ggc 768 Val Thr Thr Asp Pro Pro ProAsp Val His Val Ser Arg Val Gly Gly 245 250 255 ctg gag gac cag ctg agcgtg cgc tgg gtg tcg cca ccc gcc ctc aag 816 Leu Glu Asp Gln Leu Ser ValArg Trp Val Ser Pro Pro Ala Leu Lys 260 265 270 gat ttc ctc ttt caa gccaaa tac cag atc cgc tac cga gtg gag gac 864 Asp Phe Leu Phe Gln Ala LysTyr Gln Ile Arg Tyr Arg Val Glu Asp 275 280 285 agt gtg gac tgg aag gtggtg gac gat gtg agc aac cag acc tcc tgc 912 Ser Val Asp Trp Lys Val ValAsp Asp Val Ser Asn Gln Thr Ser Cys 290 295 300 cgc ctg gcc ggc ctg aaaccc ggc acc gtg tac ttc gtg caa gtg cgc 960 Arg Leu Ala Gly Leu Lys ProGly Thr Val Tyr Phe Val Gln Val Arg 305 310 315 320 tgc aac ccc ttt ggcatc tat ggc tcc aag aaa gcc ggg atc tgg agt 1008 Cys Asn Pro Phe Gly IleTyr Gly Ser Lys Lys Ala Gly Ile Trp Ser 325 330 335 gag tgg agc cac cccaca gcc gcc tcc act ccc cgc agt gag cgc ccg 1056 Glu Trp Ser His Pro ThrAla Ala Ser Thr Pro Arg Ser Glu Arg Pro 340 345 350 ggc ccg ggc ggc ggggcg tgc gaa ccg cgg ggc gga gag ccg agc tcg 1104 Gly Pro Gly Gly Gly AlaCys Glu Pro Arg Gly Gly Glu Pro Ser Ser 355 360 365 ggg ccg gtg cgg cgcgag ctc aag cag ttc ctg ggc tgg ctc aag aag 1152 Gly Pro Val Arg Arg GluLeu Lys Gln Phe Leu Gly Trp Leu Lys Lys 370 375 380 cac gcg tac tgc tccaac ctc agc ttc cgc ctc tac gac cag tgg cga 1200 His Ala Tyr Cys Ser AsnLeu Ser Phe Arg Leu Tyr Asp Gln Trp Arg 385 390 395 400 gcc tgg atg cagaag tcg cac aag acc cgc aac cag cac agg acg agg 1248 Ala Trp Met Gln LysSer His Lys Thr Arg Asn Gln His Arg Thr Arg 405 410 415 gga tcc tgc cctcgg gca gac ggg gca cgg cga gag gtc ctg cca gat 1296 Gly Ser Cys Pro ArgAla Asp Gly Ala Arg Arg Glu Val Leu Pro Asp 420 425 430 aag ctg tag 1305Lys Leu 4 434 PRT HUMAN 4 Arg Pro Pro Pro Leu Leu Pro Leu Leu Leu LeuLeu Cys Val Leu Gly 1 5 10 15 Ala Pro Arg Ala Gly Ser Gly Ala His ThrAla Val Ile Ser Pro Gln 20 25 30 Asp Pro Thr Leu Leu Ile Gly Ser Ser LeuLeu Ala Thr Cys Ser Val 35 40 45 His Gly Asp Pro Pro Gly Ala Thr Ala GluGly Leu Tyr Trp Thr Leu 50 55 60 Asn Gly Arg Arg Leu Pro Pro Glu Leu SerArg Val Leu Asn Ala Ser 65 70 75 80 Thr Leu Ala Leu Ala Leu Ala Asn LeuAsn Gly Ser Arg Gln Arg Ser 85 90 95 Gly Asp Asn Leu Val Cys His Ala ArgAsp Gly Ser Ile Leu Ala Gly 100 105 110 Ser Cys Leu Tyr Val Gly Leu ProPro Glu Lys Pro Val Asn Ile Ser 115 120 125 Cys Trp Ser Lys Asn Met LysAsp Leu Thr Cys Arg Trp Thr Pro Gly 130 135 140 Ala His Gly Glu Thr PheLeu His Thr Asn Tyr Ser Leu Lys Tyr Lys 145 150 155 160 Leu Arg Trp TyrGly Gln Asp Asn Thr Cys Glu Glu Tyr His Thr Val 165 170 175 Gly Pro HisSer Cys His Ile Pro Lys Asp Leu Ala Leu Phe Thr Pro 180 185 190 Tyr GluIle Trp Val Glu Ala Thr Asn Arg Leu Gly Ser Ala Arg Ser 195 200 205 AspVal Leu Thr Leu Asp Ile Leu Asp Val Gly Ser His Leu Pro Leu 210 215 220Pro Ser Pro Ala Thr Pro Gly Leu Ser Leu Leu Val Arg Gly Lys Val 225 230235 240 Val Thr Thr Asp Pro Pro Pro Asp Val His Val Ser Arg Val Gly Gly245 250 255 Leu Glu Asp Gln Leu Ser Val Arg Trp Val Ser Pro Pro Ala LeuLys 260 265 270 Asp Phe Leu Phe Gln Ala Lys Tyr Gln Ile Arg Tyr Arg ValGlu Asp 275 280 285 Ser Val Asp Trp Lys Val Val Asp Asp Val Ser Asn GlnThr Ser Cys 290 295 300 Arg Leu Ala Gly Leu Lys Pro Gly Thr Val Tyr PheVal Gln Val Arg 305 310 315 320 Cys Asn Pro Phe Gly Ile Tyr Gly Ser LysLys Ala Gly Ile Trp Ser 325 330 335 Glu Trp Ser His Pro Thr Ala Ala SerThr Pro Arg Ser Glu Arg Pro 340 345 350 Gly Pro Gly Gly Gly Ala Cys GluPro Arg Gly Gly Glu Pro Ser Ser 355 360 365 Gly Pro Val Arg Arg Glu LeuLys Gln Phe Leu Gly Trp Leu Lys Lys 370 375 380 His Ala Tyr Cys Ser AsnLeu Ser Phe Arg Leu Tyr Asp Gln Trp Arg 385 390 395 400 Ala Trp Met GlnLys Ser His Lys Thr Arg Asn Gln His Arg Thr Arg 405 410 415 Gly Ser CysPro Arg Ala Asp Gly Ala Arg Arg Glu Val Leu Pro Asp 420 425 430 Lys Leu

What is claimed is:
 1. An isolated nucleic acid molecule encoding HUMANOCR1.
 2. An isolated nucleic acid molecule according to claim 1, havinga sequence selected from the group consisting of: (a) the nucleotidesequence comprising the coding region of the HUMAN OCR1 as set forth inSEQ. NO. 3; (b) a nucleotide sequence that hybridizes under stringentconditions to the nucleotide sequence of (a) and which encodes amolecule having the biological activity of the HUMAN OCR1; or (c) anucleotide sequence which, but for the degeneracy of the genetic codewould hybridize to a nucleotide sequence of (a) or (b), and whichencodes a molecule having the biological activity of the HUMAN OCR1. 3.A vector which comprises a nucleic acid molecule of claim
 1. 4. A vectoraccording to claim 3, wherein the nucleic acid molecule is operativelylinked to an expression control sequence capable of directing itsexpression in a host cell.
 5. An isolated nucleic acid molecule encodinga MAMMALIAN OCR1.
 6. Isolated MAMMALIAN OCR1 polypeptide.
 7. IsolatedHUMAN OCR1 polypeptide encoded by the nucleic acid molecule of claim 2.8. A host-vector system for the production of HUMAN OCR1 polypeptidewhich comprises a vector of claim 4, in a host cell.
 9. A host-vectorsystem according to claim 8, wherein the host cell is a bacterial,yeast, insect or mammalian cell.
 10. A method of producing HUMAN OCR1polypeptide which comprises growing cells of a host-vector system ofclaim 9, under conditions permitting the production of HUMAN OCR1polypeptide and recovering the HUMAN OCR1 polypeptide so produced. 11.An antibody which specifically binds OCR1 polypeptide of claim
 6. 12. Anantibody according to claim 11, which is a monoclonal antibody.
 13. Acomposition comprising HUMAN OCR1 polypeptide according to claim 7 and acarrier.
 14. A composition comprising an antibody according to claim 11,and a carrier.
 15. A polypeptide comprising the extracellular portion ofthe MAMMALIAN OCR1 polypeptide fused to an immunoglobuin constantregion.
 16. The polypeptide of claim 15, wherein the constant region isthe human immunoglobulin gamma-1 constant region.
 17. A polypeptidecomprising the extracellular portion of the MAMMALIAN OCR1 polypeptidefused to an immunoglobulin Fc region.
 18. The polypeptide of claim 17,wherein the Fc region is the human immunoglobulin gamma-1 Fc region.